Vanilloid receptor ligands and their use in treatments

ABSTRACT

bis-Bicyclic amides and derivatives thereof and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

This application claims the benefit of U.S. Provisional Application No.60/538,700, filed Jan. 23, 2004, which is hereby incorporated byreference.

BACKGROUND

The vanilloid receptor 1 (VR1) is the molecular target of capsaicin, theactive ingredient in hot peppers. Julius et al. reported the molecularcloning of VR1 (Caterina et al., 1997). VR1 is a non-selective cationchannel which is activated or sensitized by a series of differentstimuli including capsaicin and resiniferatoxin (exogenous activators),heat & acid stimulation and products of lipid bilayer metabolism,anandamide (Premkumar et al., 2000, Szabo et al., 2000, Gauldie et al.,2001, Olah et al., 2001) and lipoxygenase metabolites (Hwang et al.,2000). VR1 is highly expressed in primary sensory neurons (Caterina etal., 1997) in rats, mice and humans (Onozawa et al., 2000, Mezey et al.,2000, Helliwell et al., 1998, Cortright et al., 2001). These sensoryneurons innervate many visceral organs including the dermis, bones,bladder, gastrointestinal tract and lungs; VR1 is also expressed inother neuronal and non-neuronal tissues including but not limited to,CNS nuclei, kidney, stomach and T-cells (Nozawa et al., 2001, Yiangou etal., 2001, Birder et al., 2001). Presumably expression in these variouscells and organs may contribute to their basic properties such ascellular signaling and cell division.

Prior to the molecular cloning of VR1, experimentation with capsaicinindicated the presence of a capsaicin sensitive receptor, which couldincrease the activity of sensory neurons in humans, rats and mice(Holzer, 1991; Dray, 1992, Szallasi and Blumberg 1996, 1999). The resultof acute activation by capsaicin in humans was pain at injection siteand in other species increased behavioral sensitivity to sensory stimuli(Szallasi and Blumberg, 1999). Capsaicin application to the skin inhumans causes a painful reaction characterized not only by theperception of heat and pain at the site of administration but also by awider area of hyperalgesia and allodynia, two characteristic symptoms ofthe human condition of neuropathic pain (Holzer, 1991). Taken together,it seems likely that increased activity of VR1 plays a significant rolein the establishment and maintenance of pain conditions. Topical orintradermal injection of capsaicin has also been shown to producelocalized vasodilation and edema production (Szallasi and Blumberg 1999,Singh et al., 2001). This evidence indicates that capsaicin through it'sactivation of VR1 can regulate afferent and efferent function of sensorynerves. Sensory nerve involvement in diseases could therefore bemodified by molecules, which affect the function of the vanilloidreceptor to increase or decrease the activity of sensory nerves.

VR1 gene knockout mice have been shown to reduce sensory sensitivity tothermal and acid stimuli (Caterina et al., 2000)). This supports theconcept that VR1 contributes not only to generation of pain responses(i.e. via thermal, acid or capsaicin stimuli) but also to themaintenance of basal activity of sensory nerves. This evidence agreeswith studies demonstrating capsaicin sensitive nerve involvement indisease. Primary sensory nerves in humans and other species can be madeinactive by continued capsaicin stimulation. This paradigm causesreceptor activation induced desensitization of the primary sensorynerve—such reduction in sensory nerve activity in vivo makes subjectsless sensitive to subsequent painful stimuli. In this regard bothcapsaicin and resinferatoxin (exogenous activators of VR1), producedesensitization and they have been used for many proof of conceptstudies in in vivo models of disease (Holzer, 1991, Dray 1992, Szallasiand Blumberg 1999).

BIBLIOGRAPHY

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SUMMARY

The present invention comprises a new class of compounds useful in thetreatment of diseases, such as vanilloid-receptor-mediated diseases andother maladies, such as inflammatory or neuropathic pain and diseasesinvolving sensory nerve function such as asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis. In particular, the compounds of the inventionare useful for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders. Accordingly, the inventionalso comprises pharmaceutical compositions comprising the compounds,methods for the treatment of vanilloid-receptor-mediated diseases, suchas inflammatory or neuropathic pain, asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis diseases, using the compounds and compositions ofthe invention, and intermediates and processes useful for thepreparation of the compounds of the invention.

The compounds of the invention are represented by the following generalstructure:

or a pharmaceutically acceptable salt thereof, wherein J, R¹, and R²,are defined below.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents, patent applications and other publications recitedherein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

One aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt or hydrate thereof, wherein:

-   -   J is ═O, ═S, ═CHNO₂, ═N—CN, ═CHSO₂R^(b), ═NSO₂R^(b) or ═NR^(b);    -   R¹ is a saturated, partially saturated or unsaturated 9-, 10- or        11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms        selected from N, O and S, wherein the number of O and S atoms in        the ring is not greater than 2, wherein the carbon atoms of the        ring are substituted by 0, 1 or 2 oxo groups, and wherein the        bicyclic ring is substituted by 1, 2 or 3 substituents selected        from R^(e), R^(g), C₁₋₄haloalkyl, halo, cyano, nitro,        —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆akylOR^(a); with the        proviso that bicyclic ring is not thieno[2,3-b]pyridin-2-yl;    -   R² is a saturated, partially saturated or unsaturated 9- or        10-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0,        1 or 2 atoms selected from O and S, and the bicyclic ring        contains at least one N, O or S atom, and when the bicyclic ring        is a 10-membered bicyclic ring then the ring containing the        connecting atom where R² is attached to the general structure        must have at least one N atom, and wherein the ring is        substituted by 0, 1 or 2 oxo groups; wherein the bicyclic ring        is substituted by 0, 1, 2 or 3 substituents selected from R^(e),        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),        —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), N(R^(a))S(═O)₂ NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); or R² is        a saturated or partially saturated 9- or 10-membered bicyclic        carbocyclic ring substituted by 0, 1 or 2 oxo groups and        substituted by 1, 2 or 3 substituents selected from R^(e),        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),        —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);    -   R^(a) is independently, at each instance, H or R^(b);    -   R^(b) is independently, at each instance, phenyl, benzyl or        C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by        0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,        C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,        —N(C₁₋₄alkyl)C₁₋₄alkyl;    -   R^(d) is independently at each instance C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),        —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);    -   R^(e) is independently at each instance C₁₋₆alkyl substituted by        0, 1, 2 or 3 substituents independently selected from Rd and        additionally substituted by 0 or 1 substituents selected from        R^(g);    -   R^(g) is independently at each instance a saturated, partially        saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-,        7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2,        3 or 4 atoms selected from N, O and S, wherein the carbon atoms        of the ring are substituted by 0, 1 or 2 oxo groups and the ring        is substituted by 0, 1, 2 or 3 substituents selected from        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and    -   R^(i) is benzyl, C₂₋₆alkyl, the benzyl and C₂₋₆alkyl being        substituted by 0, 1, 2 or 3 substituents selected from halo,        C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,        —N(C₁₋₄alkyl)C₁₋₄alkyl; or R^(i) is methyl substituted by 1, 2        or 3 substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl,        —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl; or        R^(i) is a saturated, partially saturated or unsaturated 5-, 6-        or 7-membered ring containing 0, 1, 2, 3 or 4 atoms selected        from N, O and S, wherein the carbon atoms of the ring are        substituted by 0, 1 or 2 oxo groups and the ring is substituted        by 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),        —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂ NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above and belowembodiments, R¹ is a saturated, partially saturated or unsaturated 9-,10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atomsselected from N and O, wherein the number of O atoms in the ring is notgreater than 2, wherein the carbon atoms of the ring are substituted by0, 1 or 2 oxo groups, and wherein the bicyclic ring is substituted by 1,2 or 3 substituents selected from R^(e), R^(g), C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above and belowembodiments, R¹ is a saturated, partially saturated or unsaturated 9-,10- or 11-membered bicyclic ring containing 1, 2, 3 or 4 atoms selectedfrom N and O, wherein the number of O atoms in the ring is not greaterthan 2, wherein the carbon atoms of the ring are substituted by 0, 1 or2 oxo groups, and wherein the bicyclic ring is substituted by 1, 2 or 3substituents selected from R^(e), R^(g), C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above and belowembodiments, R¹ is a saturated, partially saturated or unsaturated 9-,10- or 11-membered bicyclic ring containing 1, 2 or 3 N atoms, whereinthe carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups,and wherein the bicyclic ring is substituted by 1, 2 or 3 substituentsselected from R^(e), R^(g), C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(i), —OC(═O)R^(b), —C(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above and belowembodiments, R¹ is naphthyl substituted by 1, 2 or 3 substituentsselected from R^(e), R^(g), C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(i), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂ NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above and belowembodiments, R¹ is a saturated, partially saturated or unsaturated 9-,10- or 11-membered bicyclic ring containing 1 atom selected from N, Oand S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2oxo groups, and wherein the bicyclic ring is substituted by 1, 2 or 3substituents selected from R^(e), R^(g), C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b), —C(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above and belowembodiments,

-   -   R¹ is selected from        -   any of which are substituted by 1, 2 or 3 substituents            selected from R^(e), R^(g), C₁₋₄haloalkyl, halo, cyano,            nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),            —C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b),            —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),            —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a),            —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),            —S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),            —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),            —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),            —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),            —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂ NR^(a)R^(a),            —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);    -   X is independently in each instance N or C; and    -   Y is independently in each instance C, N, O or S.

In another embodiment, in conjunction with any of the above and belowembodiments,

-   -   R¹ is        both of which are substituted by 1, 2 or 3 substituents selected        from R^(e), R^(g), C₁₋₄haloalkyl, halo, cyano, nitro,        —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂ NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); and    -   X is independently in each instance N or C.

In another embodiment, in conjunction with any of the above and belowembodiments,

-   -   R¹ is selected from        -   any of which are substituted by 1, 2 or 3 substituents            selected from R^(e), R^(g), C₁₋₄haloalkyl, halo, cyano,            nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),            —C(═NR^(a))NR^(a)R^(a), —OR, —OC(═O)R^(b),            —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),            —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a),            —S(═O)R^(a), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),            —S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),            —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),            —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),            —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),            —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂ NR^(a)R^(a),            —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);    -   X is independently in each instance N or C; and    -   Y is independently in each instance C, N, O or S.

In another embodiment, in conjunction with any of the above and belowembodiments, R² is a saturated, partially saturated or unsaturated9-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2atoms selected from O and S, and the bicyclic ring contains at least oneN, O or S atom, and wherein the ring is substituted by 0, 1 or 2 oxogroups; wherein the bicyclic ring is substituted by 0, 1, 2 or 3substituents selected from R^(e), C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above and belowembodiments, R² is a saturated, partially saturated or unsaturated10-membered bicyclic ring containing 1, 2 or 3 N atoms and 0, 1 or 2atoms selected from O and S, and the bicyclic ring contains at least oneN, O or S atom, wherein the ring containing the connecting atom where R²is attached to the general structure must have at least one N atom, andwherein the ring is substituted by 0, 1 or 2 oxo groups; wherein thebicyclic ring is substituted by 0, 1, 2 or 3 substituents selected fromR^(e), C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above and belowembodiments, R² is a saturated or partially saturated 9- or 10-memberedbicyclic carbocyclic ring substituted by 0, 1 or 2 oxo groups andsubstituted by 1, 2 or 3 substituents selected from R^(e),C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above and belowembodiments, R² is bicyclic ring selected from

wherein

represents a single or double bond; and wherein the bicyclic ring issubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);

-   -   X is independently in each instance N or C; and    -   Y is independently in each instance C, N, O or S.

In another embodiment, in conjunction with any of the above and belowembodiments, R² is bicyclic ring selected from

wherein

represents a single or double bond; and wherein the bicyclic ring issubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);

-   -   X is independently in each instance N or C; and    -   Y is independently in each instance C, N, O or S.

In another embodiment, in conjunction with any of the above and belowembodiments, R² is bicyclic ring selected from

wherein

represents a single or double bond; and wherein the bicyclic ring issubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);

-   -   X is independently in each instance N or C; and    -   Y is independently in each instance C, N, O or S.

In another embodiment, in conjunction with any of the above and belowembodiments, R² is bicyclic ring selected from

wherein

represents a single or double bond; and wherein the bicyclic ring issubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a);

-   -   X is independently in each instance N or C; and    -   Y is independently in each instance C, N, O or S.

In another embodiment, in conjunction with any of the above and belowembodiments, J is ═O or ═S.

In another embodiment, in conjunction with any of the above and belowembodiments, J is ═CHNO₂ or ═CHSO₂R^(b).

In another embodiment, in conjunction with any of the above and belowembodiments, J is ═N—CN, ═NSO₂R^(b) or ═NR^(b).

Another aspect of the invention relates to a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according toany of the above embodiments.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound according to any of the above embodiments and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments in the manufacture of amedicament for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

“C_(α-β)alkyl” means an alkyl group comprising a minimum of α and amaximum of β carbon atoms in a branched, cyclical or linear relationshipor any combination of the three, wherein α and β represent integers. Thealkyl groups described in this section may also contain one or twodouble or triple bonds. Examples of C₁₋₆alkyl include, but are notlimited to the following:

“Benzo group”, alone or in combination, means the divalent radicalC₄H₄═, one representation of which is —CH═CH—CH═CH—, that when vicinallyattached to another ring forms a benzene-like ring—for exampletetrahydronapthalene, indole and the like.

The terms “oxo” and “thioxo” represent the groups ═O (as in carbonyl)and ═S (as in thiocarbonyl), respectively.

“Halo” or “halogen” means a halogen atoms selected from F, Cl, Br and I.

“C_(V-W)haloalkyl” means an alkyl group, as described above, wherein anynumber—at least one—of the hydrogen atoms attached to the alkyl chainare replaced by F, Cl, Br or I.

“Heterocycle” means a ring comprising at least one carbon atom and atleast one other atom selected from N, O and S. Examples of heterocyclesthat may be found in the claims include, but are not limited to, thefollowing:

“Available nitrogen atoms” are those nitrogen atoms that are part of aheterocycle and are joined by two single bonds (e.g. piperidine),leaving an external bond available for substitution by, for example, Hor CH₃.

“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66: 1 (1977).

“Saturated or unsaturated” includes substituents saturated withhydrogens, substituents completely unsaturated with hydrogens andsubstituents partially saturated with hydrogens.

“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl,phthaloyl and the like. A mixture of protecting groups can be used toprotect the same amino group, such as a primary amino group can beprotected by both an aralkyl group and an aralkoxycarbonyl group. Aminoprotecting groups can also form a heterocyclic ring with the nitrogen towhich they are attached, for example, 1,2-bis(methylene)benzene,phthalimidyl, succinimidyl, maleimidyl and the like and where theseheterocyclic groups can further include adjoining aryl and cycloalkylrings. In addition, the heterocyclic groups can be mono-, di- ortrisubstituted, such as nitrophthalimidyl. Amino groups may also beprotected against undesired reactions, such as oxidation, through theformation of an addition salt, such as hydrochloride, toluenesulfonicacid, trifluoroacetic acid and the like. Many of the amino protectinggroups are also suitable for protecting carboxy, hydroxy and mercaptogroups. For example, aralkyl groups. Alkyl groups are also suitablegroups for protecting hydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-trisilyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′=O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

EXPERIMENTAL

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. All parts are by weightand temperatures are in degrees centigrade unless otherwise indicated.All microwave assisted reactions were conducted with a Smith Synthesizerfrom Personal Chemistry, Uppsala, Sweden. All compounds showed NMRspectra consistent with their assigned structures. Melting points weredetermined on a Buchi apparatus and are uncorrected. Mass spectral datawas determined by electrospray ionization technique. All examples werepurified to >90% purity as determined by high-performance liquidchromatography. Unless otherwise stated, reactions were run at roomtemperature.

The following abbreviations are used:

-   DMSO—dimethyl sulfoxide-   DMF—N,N-dimethylformamide-   THF—tetrahydrofuran-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   MeOH—methyl alcohol-   EtOH—ethyl alcohol-   MeCN—acetonitrile-   MeI—iodomethane-   NMP—1-methyl-2-pyrrolidinone-   DCM—dichloromethane-   TFA—trifuoroacetic acid-   Sat.—saturated-   h—hour-   min—minutes

Example 1

(a) 6-Bromo-naphthalene-2-carbonyl chloride. To a mixture of6-bromo-naphthalene-2-carboxylic acid (1 g, 3.9 mmol, Lancaster) andCH₂Cl₂ (25 mL) was added oxalyl chloride (2.98 mL, 2 M solution inCH₂Cl₂, 5.8 mmol, Aldrich) and DMF (2 drops) with stirring at 0° C. Thereaction mixture was stirred at room temperature for 18 h and thesolvents were removed in vacuo to afford the title compound as alight-brown amorphous solid, which was used in the next step withouthpurification. MS (ESI, pos. ion) m/z: 266 (M+1).

(b) 6-Bromo-N-(1H-indol-7-yl)-2-naphthalenecarboxamide. A mixture of6-bromo-naphthalene-2-carbonyl chloride, Example 1(a), (100 mg, 0.37mmol), 7-aminoindole (98 mg, 0.74 mmol, Lancaster), dimethylaminopyridine (20 mg, Aldrich) and pyridine (3 mL) was stirred at roomtemperature for 18 h. The reaction mixture was evaporated in vacuo andthe residue was dissolved in DMSO, and purified by preparative HPLC(gradient 0.1% trifluoroacetic acid in acetonitrile) to provide thetitle compound as a brown amorphous solid. MS (ESI, pos. ion) m/z: 366(M+1).

Example 2

(2R)-6-Bromo-N-(2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl)-2-naphthalenecarboxamide.This material was prepared analogous to the procedure described forExample 1(b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a),(127 mg, 0.47 mmol) reacted with(2R)-(6-amino-2,3-dihydrobenzol[1,4]dioxin-2-yl)methanol (85.6 mg, 0.47mmol, prepared according to the procedure described in WO03099284) togive the title compound as a dark-brown amorphous solid. MS (ESI, pos.ion.) m/z: 416 (M+1).

Example 3

6-Bromo-naphthalene-2-carboxylic acid (2-amino-benzothiazol-4-yl)-amide.This material was prepared analogous to the procedure described forExample 1(b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a),(127 mg, 0.47 mmol) reacted with benzothiazole-2,4-diamine (77 mg, 0.47mmol, prepared according to the procedure described in WO03099284) togive the title compound as an amorphous solid. MS (ESI, pos. ion.) m/z:400 (M+1).

Example 4

6-Bromo-naphthalene-2-carboxylic acid(2-acetylamino-benzothiazol-4-yl)-amide. This material was preparedanalogous to the procedure described for Example 1(b).6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a), (98 mg, 0.36mmol) reacted with N-(4-amino-benzothiazol-2-yl)-acetamide (50 mg, 0.24mmol, prepared according to the procedure described in WO03099284) togive the title compound as a solid. Mp 241.6° C. MS (ESI, pos. ion.)m/z: 441 (M+1).

Example 5

6-Bromo-naphthalene-2-carboxylic acid (1H-benzoimidazol-5-yl)-amide.This material was prepared analogous to the procedure described forExample 1 (b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a),reacted with 1H-benzoimidazol-5-ylamine (TimTec) to give the titlecompound as an amorphous solid. MS (ESI, pos. ion.) m/z: 366 (M+1).

Example 6

6-Bromo-naphthalene-2-carboxylic acid quinolin-3-ylamide. This materialwas prepared analogous to the procedure described for Example 1(b).6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a), reacted with3-aminoquinoline (Aldrich) to give the title compound as a greenamorphous solid. MS (ESI, pos. ion.) m/z: 377 (M+1).

Example 7

(a) 6-Trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride. Thismaterial was prepared analogous to the procedure described for Example1(a). 6-Trifluoromethyl-benzo[b]thiophene-2-carboxylic acid (220 mg,0.89 mmol, prepared according to the procedure described in EP483647)reacted with oxalyl chloride (0.89 mL, 2 M solution in CH₂Cl₂, 1.78mmol, Aldrich) to give the the crude title compound as an off-whitesolid, which was used in the next step without purification.

(b)N-(5-Trifluoromethyl-pyridin-2-yl)-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide.This material was prepared analogous to the procedure described forExample 1(b) by reacting 6-trifluoromethyl-benzo[b]thiophene-2-carbonylchloride, Example 7(a), (84 mg, 0.32 mmol) withN-(4-amino-benzothiazol-2-yl)-acetamide (52 mg, 0.25 mmol, preparedaccording to the procedure described in WO03099284). Purification of thecrude product by silica gel column chromatography (gradient, 20 to 60%EtOAc/hexane) provided the title compound as a light-yellow solid. Mp285.4-285.9° C. MS (ESI, pos. ion.) m/z: 436 (M+1).

Example 8

(a) 1-Isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carbonyl chloridehydrochloride. This material was prepared analogous to the proceduredescribed for Example 1 (a), by reacting1-isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid (414mg, 1.52 mmol, Oakwood) with oxalyl chloride (1.52 mL, 2 M solution inCH₂Cl₂, 3.04 mmol, Aldrich). The crude title compound was isolated as anoff-white solid and used in the next step without purification.

(b) 1-Isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid(2-acetylamino-benzothiazol-4-yl)-amide. This material was preparedanalogous to the procedure described for Example 1 (b) by reacting1-isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carbonyl chloridehydrochloride, Example 8(a), (83 mg, 0.28 mmol) withN-(4-amino-benzothiazol-2-yl)-acetamide (50 mg, 0.24 mmol, preparedaccording to the procedure described in WO03099284). The crude productwas purified by silica gel column chromatography (gradient, 50 to 90%EtOAc/hexane) to afford the title compound as as a white film. MS (ESI,pos. ion.) m/z: 462 (M+1).

Example 9

(a) 1,3-Dioxo-1,3-dihydro-isobenzofuran-5-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide. A mixture of trimelliticanhydride chloride (2.1 g, 9.97 mmol, Aldrich) and1,4-benzodioxan-6-amine (1.5 g, 9.98 mmol, Aldrich) in dichlorobenzene(20 mL) was heated at 150° C. with stirring for 2 h. The reactionmixture was left to reach room temperature during which an yellow solidprecipitated. The solid was filtered, washed with dichlorobenzene (20mL) and dichloromethane (20 mL), and dried in vacuo to give the titlecompound as an yellow amorphous solid. MS (ESI, pos. ion) m/z: 326.5(M+1).

(b) 2-tert-Butyl-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide. tert-Butylamine (0.21 mL, 2mmol, Aldrich) was added dropwise to a solution of1,3-dioxo-1,3-dihydro-isobenzofuran-5-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide (0.65 g, 2 mmol) in glacialAcOH (3 mL) and DMSO (1 mL) with stirring at room temperature. Themixture was stirred at room temperature for 1 h and heated at 110° C.with stirring under nitrogen atmosphere for 18 h. The reaction mixturewas cooled to room temperature, diluted with EtOAc (50 mL), washed withsatd. aq. NaHCO₃ solution (3×) and water, dried over Na₂SO₄ andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by silica gel column chromatography (30% EtOAc/hexane) to givethe title compound as a light-yellow solid. MS (ESI, pos. ion) m/z:381.3 (M+1).

Example 10

(a) (3S)-7-tert-Butyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid.(This material was prepared according to the method of Ma, D.; Ma, Z.;Kozikowski, A. P.; Pshenichkin, S.; Wroblewski, J. T. Bioorg. Med. Chem.Lett. 1998, 8, 2447-2450). To a 250-mL, round-bottomed flask, equippedwith magnetic stirring and reflux condenser, was added2-tert-butoxycarbonylamino-3-(4-tert-butyl-phenyl)-propionic acid (5.0g, 15.6 mmol, Bachem, Boc-p-tBu-Phe-OH), formaldehyde (50 mL, 37 wt. %in H₂O, Aldrich) and cond HCl (30 mL). The reaction mixture was heatedat 90° C. with stirring for 4 h. The reaction mixture was cooled to roomtemperature and the solvents were removed in vacuo to provide the titlecompound, which was used in the next step withouth purification. MS(ESI, pos. ion) m/z: 234 (M+1).

(b) (3S)-7-tert-Butyl-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester.(3S)-7-tert-Butyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid,Example 10(a), was dissolved in THF (140 mL) and treated with 5% aq.K₂CO₃ (140 mL) and di-t-butyl dicarbonate (4.8 g, 22 mmol, Aldrich). Thereaction mixture was stirred at 25° C. overnight and acidified to pH 5with 1 N HCl. The mixture was extracted with EtOAc (300 mL) and theorganic phase was washed with satd NaCl (100 mL) and H₂O (120 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (2:1 hexane/EtOAc) to givethe title compound. MS (ESI, neg. ion) m/z: 333 (M−1).

(c)(3S)-7-tert-Butyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester. To a 250-mL, round-bottomed flask equipped withmagnetic stirring was added(3S)-7-tert-butyl-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester, Example 10(b), (1.5 g, 4.65 mmol), DMF (15 mL),1,4-benzodioxan-6-amine (700 mg, 4.65 mmol, Aldrich),dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (1.25 g, 6.5 mmol,Aldrich) and N,N-diisopropylethylamine (2.5 mL, 13.95 mmol, Aldrich).The reaction mixture was stirred at 25° C. for 18 h and concentrated invacuo. The residue was dissolved in EtOAc (35 mL), washed with H₂O (2×15mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated invacuo and the residue was purified by silica gel column chromatography(3:1 hex ane/EtOAc) to give the title compound, which was used directlyin the next step. MS (ESI, pos. ion) m/z: 467 (M+1).

(d) (3S)-7-tert-Butyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide hydrochloride. A mixture of(3S)-7-tert-butyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester, Example 10(c), and 4.0 N HCl in dioxane (10 mL,Aldrich) was stirred at 25° C. for 1 h. The solvent was removed in vacuoto provide the title compound. Mp 134° C. MS (ESI, pos. ion) m/z: 367(M+1).

Example 11

7-tert-Butyl-isoquinoline-3-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)amide. (The title product wasprepared according to the procedure of E. D. Cox; T. J. Hagen; R. M.McKernan; J. M. Cook, Med. Chem. Rest. 1995, 5, 710-718). To a solutionof (3S)-7-tert-butyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide hydrochloride, Example 10(d),(80 mg, 0.219 mmol) in toluene (10 mL) was added manganese dioxide (110mg, 1.1 mmol). The reaction mixture was stirred at 70° C. under N₂ for1.5 h, filtered through a pad of Celite®, and the filtrate wasevaporated in vacuo. The residue was purified by silica gel columnchromatography (8:1 hexane/EtOAc) to give the title compound as anyellow solid. Mp 154-157° C. MS (ESI, pos. ion) m/z: 363 (M+1).

Example 12

(a) 6-Trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylic acid. To a250-mL, round-bottomed flask, equipped with magnetic stirring, was addedethyl 6-(trifluoromethyl)-thieno-[3,2-b]-pyrimidine-2-carboxylate (1.0g, 3.6 mmol, Maybridge), 5 N NaOH (8 mL) and THF (8 mL). The reactionmixture was stirred at room temperature for 7 h. The mixture wasacidified to pH 5 by adding 10% HCl and the product was extracted withEtOAc (25 mL). The organic phase was washed with H₂O (2×15 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to yield the titlecompound as a white solid. MS (ESI, pos. ion) m/z: 248 (M+1).

(b) 6-Trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide. This material was preparedanalogous to the procedure described for Example 10(c).6-Trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylic acid, Example12(a), (0.20 g, 0.81 mmol) reacted with 1,4-benzodioxan-6-amine (0.12 g,0.81 mmol, Aldrich) to give the title compound as an yellow solid. Mp247° C. MS (ESI, pos. ion) m/z: 381 (M+1).

Example 13

(a) Ethyl 7-(trifluoromethyl)-4-chloro-quinoline-2-carboxylate. To a250-mL round-bottomed flask, equipped with magnetic stirring, was addedethyl 7-(trifluoromethyl)-4-hydroxy-quinoline-2-carboxylate (0.60 g, 2.1mmol, Aldrich) and POCl₃ (3.9 mL, 42 mmol, Aldrich). The reactionmixture was heated at reflux under nitrogen for 3 h, cooled to roomtemperature and concentrated in vacuo. The residue was taken in EtOAc(100 mL) and was washed with 5% Na₂CO₃ (40 mL), H₂O (40 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to yield the title compound.MS (ESI, pos. ion) m/z: 304 (M+1).

(b) 4-Chloro-7-trifluoromethyl-quinoline-3-carboxylic acid. Thismaterial was prepared analogous to the procedure described for Example12(a). Ethyl 7-(trifluoromethyl)-4-chloro-quinoline-2-carboxylate,Example 13(a), (0.60 g, 2.0 mmol) reacted with 1 N NaOH (10 mL, 10 mmol)to give the title compound. MS (ESI, pos. ion) m/z: 276 (M+1).

(c) 4-Chloro-7-trifluoromethyl-quinoline-3-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide. This material was preparedanalogous to the procedure described for Example 10 (c).4-Chloro-7-trifluoromethyl-quinoline-3-carboxylic acid, Example 13(b),(0.23 g, 0.85 mmol) reacted with 1,4-benzodioxan-6-amine (0.13 g, 0.85mmol, Aldrich) to give the title compound as a light yellow solid. MP296° C. MS (ESI, pos. ion) m/z: 409 (M+1).

Example 14

6-Bromo-naphthalene-2-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide. This material was preparedanalogous to the procedure described for Example 10(c).6-Bromo-naphthalene-2-carboxylic acid (0.5 g, 2 mmol, Lancaster) reactedwith 1,4-benzodioxan-6-amine (0.332 g, 2.2 mmol, Aldrich) to give thetitle compound as a light-yellow solid. Mp 222.7° C. MS (ESI, pos. ion)m/z: 384 (M+1).

Capsaicin-Induced Ca2+ Influx in Primary Dorsal Root Ganglion Neurons

Embryonic 19 day old (E19) dorsal root ganglia (DRG) were dissected fromtimed-pregnant, terminally anesthetized Sprague-Dawley rats (CharlesRiver, Wilmington, Mass.) and collected in ice-cold L-15 media (LifeTechnologies, Grand Island, N.Y.) containing 5% heat inactivated horseserum (Life Technologies). The DRG were then dissociated into singlecell suspension using a papain dissociation system (WorthingtonBiochemical Corp., Freehold, N.J.). The dissociated cells were pelletedat 200×g for 5 min and re-suspended in EBSS containing 1 mg/ml ovomucoidinhibitor, 1 mg/ml ovalbumin and 0.005% DNase. Cell suspension wascentrifuged through a gradient solution containing 10 mg/ml ovomucoidinhibitor, 10 mg/ml ovalbumin at 200×g for 6 min to remove cell debris;and filtered through a 88-μm nylon mesh (Fisher Scientific, Pittsburgh,Pa.) to remove any clumps. Cell number was determined with ahemocytometer and cells were seeded into poly-ornithine 100 μg/ml(Sigma) and mouse laminin 1 μg/ml (Life Technologies)-coated 96-wellplates at 10×10³ cells/well in complete medium. The complete mediumconsists of minimal essential medium (MEM) and Ham's F12, 1:1,penicillin (100 U/ml), and streptomycin (100 μg/ml), and nerve growthfactor (10 ng/ml), 10% heat inactivated horse serum (Life Technologies).The cultures were kept at 37° C., 5% CO₂ and 100% humidity. Forcontrolling the growth of non-neuronal cells, 5-fluoro-2′-deoxyuridine(75 μM) and uridine (180 μM) were included in the medium. Activation ofVR1 is achieved in these cellular assays using either a capsaicinstimulus (ranging from 0.01-10 μM) or by an acid stimulus (addition of30 mM Hepes/Mes buffered at pH 4.1). Compounds are also tested in anassay format to evaluate their agonist properties at VR1.

Capsaicin Antagonist Assay: E-19 DRG cells at 5 days in culture areincubated with serial concentrations of VR1 antagonists, in HBSS (Hanksbuffered saline solution supplemented with BSA 0.1 mg/ml and 1 mM Hepesat pH 7.4) for 15 min, 37° C. Cells are then challenged with a VR1agonist, capsaicin 200 nM, in activation buffer containing 0.1 mg/mlBSA, 15 mM Hepes, pH 7.4, and 10 μCi/ml ⁴⁵Ca²⁺ (Amersham) in Ham's F12for 2 min at 37° C.

Acid Antagonist Assay: Compounds are pre-incubated with E-19 DRG cellsfor 2 minutes prior to addition of Calcium-45 in 30 mM Hepes/Mes buffer(Final Assay pH 5) and then left for an additional 2 minutes prior tocompound washout. Final 45Ca (Amersham CES3-2 mCi) at 10 μCi/mL.

Agonist Assay: Compounds are incubated with E-19 DRG cells for 2 minutesin the presence of Calcium-45 prior to compound washout. Final ⁴⁵Ca²⁺(Amersham CES3-2 mCi) at 10 μCi/mL.

Compound Washout and Analysis: Assay plates are washed using an ELX405plate washer (Bio-Tek Instruments Inc.) immediately after functionalassay. Wash 3× with PBS Mg2+/Ca2+ free, 0.1 mg/mL BSA. Aspirate betweenwashes. Read plates using a MicroBeta Jet (Wallac Inc.). Compoundactivity is then calculated using appropriate computational algorithms.

⁴⁵Calcium²⁺ Assay Protocol

Compounds may be assayed using Chinese Hamster Ovary cell lines stablyexpressing either human VR1 or rat VR1 under a CMV promoter. Cells canbe cultured in Growth Medium, routinely passaged at 70% confluency usingtrypsin and plated in the assay plate 24 hours prior to compoundevaluation.

Possible Growth Medium:

-   -   DMEM, high glucose (Gibco 11965-084).    -   10% Dialyzed serum (Hyclone SH30079.03).    -   1× Non-Essential Amino Acids (Gibco 11140-050).    -   1× Glutamine-Pen-Strep (Gibco 10378-016).    -   Geneticin, 450 μg/mL (Gibco 10131-035).

Compounds can be diluted in 100% DMSO and tested for activity overseveral log units of concentration [40 μM-2 pM]. Compounds may befurther diluted in HBSS buffer (pH 7.4) 0.1 mg/mL BSA, prior toevaluation. Final DMSO concentration in assay would be 0.5%. Each assayplate can be controlled with a buffer only and a known antagonistcompound (either capsazepine or one of the described VR1 antagonists).

Activation of VR1 can be achieved in these cellular assays using eithera capsaicin stimulus (ranging from 0.1-1 μM) or by an acid stimulus(addition of 30 mM Hepes/Mes buffered at pH 4.1). Compounds may alsotested in an assay format to evaluate their agonist properties at VR1.

Capsaicin Antagonist Assay: Compounds may be pre-incubated with cells(expressing either human or rat VR1) for 2 minutes prior to addition ofCalcium-45 and Capsaicin and then left for an additional 2 minutes priorto compound washout. Capsaicin (0.5 nM) can be added in HAM's F12, 0.1mg/mL BSA, 15 mM Hepes at pH 7.4. Final ⁴⁵Ca (Amersham CES3-2 mCi) at 10μCi/mL.

Acid Antagonist Assay: Compounds can be pre-incubated with cells(expressing either human or rat VR1) for 2 minutes prior to addition ofCalcium-45 in 30 mM Hepes/Mes buffer (Final Assay pH 5) and then leftfor an additional 2 minutes prior to compound washout. Final ⁴⁵Ca(Amersham CES3-2mCi) at 10 μCi/mL.

Agonist Assay: Compounds can be incubated with cells (expressing eitherhuman or rat VR1) for 2 minutes in the presence of Calcium-45 prior tocompound washout. Final ⁴⁵Ca (Amersham CES3-2mCi) at 10 μCi/mL.

Compound Washout and Analysis: Assay plates can be washed using anELX405 plate washer (Bio-Tek Instruments Inc.) immediately afterfunctional assay. One can wash 3× with PBS Mg2+/Ca²⁺ free, 0.1 mg/mLBSA, aspirating between washes. Plates may be read using a MicroBeta Jet(Wallac Inc.). Compound activity may then calculated using appropriatecomputational algorithms.

Useful nucleic acid sequences and proteins may be found in U.S. Pat.Nos. 6,335,180, 6, 406,908 and 6,239,267, herein incorporated byreference in their entirety.

For the treatment of vanilloid-receptor-diseases, such as acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, the compounds of the present invention may be administeredorally, parentally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. The term parenteral asused herein includes, subcutaneous, intravenous, intramuscular,intrasternal, infusion techniques or intraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, pain, inflammation and the like.

The dosage regimen for treating vanilloid-receptor-mediated diseases,cancer, and/or hyperglycemia with the compounds of this invention and/orcompositions of this invention is based on a variety of factors,including the type of disease, the age, weight, sex, medical conditionof the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one which is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention, may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, α-methoxyethyl, groups such asα-((C₁-C₄)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethylformamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes, which are obvious to one skilled in the art, are intendedto be within the scope and nature of the invention, which are defined,in the appended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound having the structure:

or any pharmaceutically-acceptable salt or hydrate thereof, wherein: Jis ═O, ═S, ═CHNO₂, ═N—CN, ═CHSO₂R^(b), ═NSO₂R^(b) or ═NR^(b); R¹ is asaturated, partially saturated or unsaturated 9-, 10- or 11-memberedbicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,wherein the number of O and S atoms in the ring is not greater than 2,wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxogroups, and wherein the bicyclic ring is substituted by 1, 2 or 3substituents selected from R^(e), R^(g), C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); withthe proviso that bicyclic ring is not thieno[2,3-b]pyridin-2-yl; R² is asaturated, partially saturated or unsaturated 9- or 10-membered bicyclicring containing 0, 1, 2 or 3 N atoms and 0, 1, 2 atoms selected from Oand S, and the bicyclic ring contains at least one N, O or S atom, andwhen the bicyclic ring is a 10-membered bicyclic ring then the ringcontaining the connecting atom where R² is attached to the generalstructure must have at least one N atom, and wherein the ring issubstituted by 0, 1 or 2 oxo groups; wherein the bicyclic ring issubstituted by 0, 1, 2 or 3 substituents selected from R^(e),C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); or R² is asaturated or partially saturated 9- or 10-membered bicyclic carbocyclicring substituted by 0, 1 or 2 oxo groups and substituted by 1, 2 or 3substituents selected from R^(e), C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); R^(a) isindependently, at each instance, H or R^(b); R^(b) is independently, ateach instance, phenyl, benzyl or C₁₋₆alkyl, the phenyl, benzyl andC₁₋₆alkyl being substituted by 0, 1, 2 or 3 substituents selected fromhalo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,—N(C₁₋₄alkyl)C₁₋₄alkyl; R^(d) is independently at each instanceC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a) C₂₋₆alkylOR^(a); R^(e) isindependently at each instance C₁₋₆alkyl substituted by 0, 1, 2 or 3substituents independently selected from R^(d) and additionallysubstituted by 0 or 1 substituents selected from R^(g); R^(g) isindependently at each instance a saturated, partially saturated orunsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected fromN, O and S, wherein the carbon atoms of the ring are substituted by 0, 1or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and R¹ isbenzyl, C₂₋₆alkyl, the benzyl and C₂₋₆alkyl being substituted by 0, 1, 2or 3 substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl,—OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl; or R^(i) ismethyl substituted by 1, 2 or 3 substituents selected from halo,C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,—N(C₁₋₄alkyl)C₁₋₄alkyl; or R^(i) is a saturated, partially saturated orunsaturated 5-, 6- or 7-membered ring containing 0, 1, 2, 3 or 4 atomsselected from N, O and S, wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1,2 or 3 substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a). 2.A compound according to claim 1, wherein R¹ is a saturated, partiallysaturated or unsaturated 9-, 10- or 11-membered bicyclic ring containing0, 1, 2, 3 or 4 atoms selected from N and O, wherein the number of Oatoms in the ring is not greater than 2, wherein the carbon atoms of thering are substituted by 0, 1 or 2 oxo groups, and wherein the bicyclicring is substituted by 1, 2 or 3 substituents selected from R^(e),R^(g), C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).
 3. A compoundaccording to claim 1, wherein R¹ is a saturated, partially saturated orunsaturated 9-, 10- or 11-membered bicyclic ring containing 1, 2, 3 or 4atoms selected from N and O, wherein the number of O atoms in the ringis not greater than 2, wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups, and wherein the bicyclic ring issubstituted by 1, 2 or 3 substituents selected from R^(e), R^(g),C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).
 4. A compoundaccording to claim 1, wherein R¹ is a saturated, partially saturated orunsaturated 9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 Natoms, wherein the carbon atoms of the ring are substituted by 0, 1 or 2oxo groups, and wherein the bicyclic ring is substituted by 1, 2 or 3substituents selected from R^(e), R^(g), C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)RbN(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a).
 5. A compound according to claim 1, wherein R¹is naphthyl substituted by 1, 2 or 3 substituents selected from R^(e),R^(g), C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R, —C(═NR^(a))NR^(a)R^(a), —OR^(i), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).
 6. A compoundaccording to claim 1, wherein R¹ is a saturated, partially saturated orunsaturated 9-, 10- or 1′-membered bicyclic ring containing 1 atomselected from N, O and S, wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups, and wherein the bicyclic ring issubstituted by 1, 2 or 3 substituents selected from R^(e), R^(g),C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(i), OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).
 7. A compoundaccording to claim 1, wherein R¹ is selected from

any of which are substituted by 1, 2 or 3 substituents selected fromR^(e), R^(g), C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(i),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂ NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); X isindependently in each instance N or C; and Y is independently in eachinstance C, N, O or S.
 8. A compound according to claim 1, wherein R¹ is

both of which are substituted by 1, 2 or 3 substituents selected fromR^(e), R^(g), C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(i),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂ NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); and X isindependently in each instance N or C.
 9. A compound according to claim1, wherein R¹ is selected from

any of which are substituted by 1, 2 or 3 substituents selected fromR^(e), R^(g), C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(i),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); X isindependently in each instance N or C; and Y is independently in eachinstance C, N, O or S.
 10. A compound according to claim 1, wherein R²is a saturated, partially saturated or unsaturated 9-membered bicyclicring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from Oand S, and the bicyclic ring contains at least one N, O or S atom, andwherein the ring is substituted by 0, 1 or 2 oxo groups; wherein thebicyclic ring is substituted by 0, 1, 2 or 3 substituents selected fromR^(e), C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).
 11. A compoundaccording to claim 1, wherein R² is a saturated, partially saturated orunsaturated 10-membered bicyclic ring containing 1, 2 or 3 N atoms and0, 1 or 2 atoms selected from O and S, and the bicyclic ring contains atleast one N, O or S atom, wherein the ring containing the connectingatom where R² is attached to the general structure must have at leastone N atom, and wherein the ring is substituted by 0, 1 or 2 oxo groups;wherein the bicyclic ring is substituted by 0, 1, 2 or 3 substituentsselected from R^(e), C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).
 12. A compoundaccording to claim 1, wherein R² is a saturated or partially saturated9- or 10-membered bicyclic carbocyclic ring substituted by 0, 1 or 2 oxogroups and substituted by 1, 2 or 3 substituents selected from R^(e),C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a).
 13. A compoundaccording to claim 1, wherein R² is bicyclic ring selected from

wherein

represents a single or double bond; and wherein the bicyclic ring issubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); X isindependently in each instance N or C; and Y is independently in eachinstance C, N, O or S.
 14. A compound according to claim 1, wherein R²is bicyclic ring selected from

wherein

represents a single or double bond; and wherein the bicyclic ring issubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); X isindependently in each instance N or C; and Y is independently in eachinstance C, N, O or S.
 15. A compound according to claim 1, wherein R²is bicyclic ring selected from

wherein

represents a single or double bond; and wherein the bicyclic ring issubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂ NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a); X isindependently in each instance N or C; and Y is independently in eachinstance C, N, O or S.
 16. A compound according to claim 1, wherein R²is bicyclic ring selected from

wherein

represents a single or double bond; and wherein the bicyclic ring issubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR, —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)Rb —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a); X is independently in each instance N or C; andY is independently in each instance C, N, O or S.
 17. A compoundaccording to claim 1 selected from the group of:(3S)-7-tert-butyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide;4-chloro-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(trifluoromethyl)-3-quinolinecarboxamide;6-bromo-N-(1H-indol-7-yl)-2-naphthalenecarboxamide;6-bromo-N-(2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl)-2-naphthalenecarboxamide;6-bromo-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-naphthalenecarboxamide;6-bromo-N-(3-quinolinyl)-2-naphthalenecarboxamide;N-(1H-benzimidazol-5-yl)-6-bromo-2-naphthalenecarboxamide;N-(2-(acetylamino)-1,3-benzothiazol-4-yl)-1-(1-methylethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-carboxamide;N-(2-(acetylamino)-1,3-benzothiazol-4-yl)-6-(trifluoromethyl)-1-benzothiophene-2-carboxamide;N-(2-(acetylamino)-1,3-benzothiazol-4-yl)-6-bromo-2-naphthalenecarboxamide;N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(1,1-dimethylethyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxamide;N-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(trifluoromethyl)thieno[3,2-b]pyridine-2-carboxamide;N-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(1,1-dimethylethyl)-3-isoquinolinecarboxamide;and N-(2-amino-1,3-benzothiazol-4-yl)-6-bromo-2-naphthalenecarboxamide;or any pharmaceutically-acceptable salts or hydrates thereof.
 18. Amethod of treating acute, inflammatory and neuropathic pain, dentalpain, general headache, migraine, cluster headache, mixed-vascular andnon-vascular syndromes, tension headache, general inflammation,arthritis, rheumatic diseases, osteoarthritis, inflammatory boweldisorders, anxiety, depression, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders, comprising the step ofadministering a compound according to claim
 1. 19. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically-acceptable diluent or carrier.